Global Health Diagnostics: Research, Development and Regulation

Global health diagnostics: research, development
and regulation
Workshop report
April 2009
The Academy of Medical Sciences

The Academy of Medical Sciences promotes advances in medical science and campaigns to ensure
these are converted into healthcare benefits for society. Our Fellows are the UKs leading medical
scientists from hospitals and general practice, academia, industry and public service.
The Academy seeks to play a pivotal role in determining the future of medical science in the UK,
and the benefits that society will enjoy in years to come. We champion the UKs strengths in
medical science, promote careers and capacity building, encourage the implementation of new
ideas and solutions often through novel partnerships and help to remove barriers to progress.
ISBN No: 1-903401-20-8
Global health diagnostics: research, development

and regulation
Workshop report
April 2009
?
Global health diagnostics
Acknowledgements
This report was prepared by Dr Georgie MacArthur and is published by the Academy of Medical
Sciences. The Academy warmly thanks the Chairman, speakers and delegates for their
participation in the symposium and for their input into this report.
All web references were accessed in March 2009
Academy of Medical Sciences
contents
?
Contents
1. Background
2. Introduction
3. Design and development of diagnostic tests
4. Access to diagnostics
13
5. Use of diagnostic tests in practice
15
6. Regulation and evaluation of diagnostic tests
17
7. Challenges and opportunities for the diagnostics industry
19
Conclusions
21
Annex 1: meeting programme
25
Annex 2: delegate list
26
1. Background
?
1. Background
This report provides a summary of a workshop
Panellists included: Professor David Mabey
held by the Academy of Medical Sciences
FMedSci, London School of Hygiene and
on Global health diagnostics: research,
Tropical Medicine; Mr Jean-Franois de
development and regulation on 3 December
Lavison, European Diagnostics Manufacturers
2008 at the Wellcome Collection Conference
Association; and Dr Mark Perkins, Foundation
Centre in London. The workshop aimed to:
for Innovative New Diagnostics (FIND). The
Raise awareness of the importance of
meeting was attended by 60 invited guests
diagnostics for tackling global health issues.
representing academia, industry, medicine,
Highlight the range of barriers to research,
publishing, research funders and other
development and regulation of global
stakeholders. A full programme and delegate
health diagnostics.
list is annexed.
Highlight the latest research and

development in the field.
The Academy of Medical Sciences is extremely
Identify areas where further activity may
grateful to speakers and attendees for their
be required.
contributions to this event. This report captures

some of the key issues and themes that arose
The meeting was chaired by Sir Andy Haines
from presentations and discussions on the day,
FMedSci, Director of the London School of
including:
Hygiene and Tropical Medicine, and included
presentations and a panel discussion with key
Design and development of diagnostic tests

suitable for use in low- and middle-income
experts in the field. Presentations were given
countries (LMIC).
by: Professor Rosanna Peeling, London School
Access to diagnostics in LMIC.
of Hygiene and Tropical Medicine and UNICEF/
Use of diagnostic tests in practice.
UNDP/World Bank/WHO Special Programme
Regulation and evaluation of
for Research and Training in Tropical Diseases

(WHO/TDR); Dr Helen Lee, University of
Cambridge; and Mr Ian Boulton, TropMed
diagnostic tests.

Challenges and opportunities for the

diagnostics industry.
Pharma Consulting Ltd. Three key topics

were addressed:
The report is intended for researchers, research
Research into novel diagnostics.
funders, policymakers and other stakeholders.
Challenges to the evaluation and regulation

of novel diagnostic tests.
Perspectives from the private sector.
2. introduction
?
2. Introduction
To date, efforts to address the burden of global
Many diagnostic tests remain inappropriate
health have largely focused on the development
to the infrastructure and contexts of LMIC.
and delivery of therapeutic interventions,
A lack of access to diagnostic tests
whilst the value of diagnostics has been
The high purchase costs of many
somewhat overlooked. For instance, in 2004,
diagnostic tests preclude access by the
global investment in diagnostics represented
majority of patients in LMIC. Patients
less than 1% of the total global spending in
in LMIC also lack physical access to
tackling malaria, compared to 37% for drug
diagnostics since laboratory infrastructure
development and 24% for
vaccines.1
is often limited and the majority of

patients do not live in communities with
Yet results from diagnostic testing for infectious

diseases guide the majority of healthcare
laboratory diagnostic services.

A lack of regulatory control and quality
decisions and are therefore critical to
standards for evaluation
improving global health. In LMIC in particular,
Many tests are sold and used without any
the deployment of accurate, affordable and
evidence of clinical effectiveness due to
safe diagnostic tests has the potential to
the lack of regulatory standards, which can
revolutionise the diagnosis, monitoring and
dissuade reputable companies with quality
treatment of disease at the individual and
products from competing.
population level. Specifically, the use of
A lack of infrastructure and human
diagnostics facilitates:
resource capacity
Screening for asymptomatic infections in at
Existing infrastructure and capacity limits
risk populations, such as HIV, Hepatitis C,
the delivery and integration of novel
syphilis and chlamydia.
diagnostics into existing health systems.
Evidence-based patient management

(particularly for diseases with non-specific
As a result of these barriers, the availability of
clinical symptoms and signs, such as fever).
diagnostic testing in LMIC remains limited and
Disease surveillance and outbreak
many clinicians rely solely on the symptoms
investigations.
and clinical signs presenting in the patient.
Evaluation of the effectiveness of
This can create difficulties, particularly for
interventions and certification of disease
the management of illnesses that are caused
elimination.
by a range of pathogenic agents, and for
Detection and monitoring of drug-
latent or asymptomatic infections such as
resistance.
sexually transmitted infections (STIs). The
Facilitation of epidemiological studies to
syndromic approach to disease management
monitor disease burden and trends; and
can waste costly medicines, placing a further
of clinical trials, such as drug and vaccine
strain on budgets in resource-limited settings.
efficacy trials.
Importantly, inappropriate treatment can also

exert selection pressure on drug-resistant
However, there are a number of barriers to
variants and, in some cases, can prevent
the development and use of diagnostics for
treatment of the true cause of illness.
diseases of importance in LMIC, including:

A lack of investment and innovation
Many current diagnostic tools used in LMIC
The development of novel tests requires
require repeat visits to a clinic, which presents
substantial investment and there are few
further challenges. A substantial proportion
incentives for the commercial sector to
of patients may not return for follow up visits,
develop diagnostics of importance to LMIC.
which can lead to the development of long term
1M
alaria R&D Alliance (2005). Malaria research and development, an assessment of global investment. http://www.malariaalliance.org/pdfs/
rd_report_complete.pdf
?
G lobal health diagnostics
complications, and, in the case of infectious
testing of blood donors, which can increase
diseases such as tuberculosis (TB), HIV and
the transmission of blood-borne viruses.
STIs, can result in the continued transmission
There is also little capacity for diagnosing and
of the infectious agent to others. Appropriate
monitoring chronic non-communicable diseases
diagnostics are often unavailable for the
(NCD) in LMIC settings.
Box 1 Background to diagnostic tests

Rapid diagnostic tests (RDTs) use samples such as urine or blood from a finger prick to give
rapid visual results. Such tests provide particular promise for use in primary healthcare settings
in LMIC since they are simple to use and can often be performed without specialist equipment
or skilled personnel. RDTs mostly use immunochromatography to detect antigens or antibodies
using a lateral flow or dipstick design; or visualise antigen-antibody complexes.2
Additional diagnostic tests utilised in LMIC include microscopy, bacterial culture, enzyme
immunoassay, and nucleic acid amplification. Microscopy is frequently used to diagnose
mycobacterial or parasitic infections such as TB and malaria, using sputum or blood samples.
Culture remains the gold standard for bacterial diagnosis, but is rarely available in LMIC, and
results are not available for several days. Antibody or antigen detection assays, such as enzyme
immunoassays, are increasingly used to diagnose infectious diseases, in part, since tests are
based on the antigen-antibody interaction and results can be obtained in hours rather than days
or weeks. Assays can also be performed with relatively simple equipment.
Nucleic acid amplification tests, such as polymerase chain reaction (PCR), have high sensitivity
and specificity and, particularly for the diagnosis of sexually transmitted infections, have the
advantage of using non-invasive specimens such as urine. However, such tests are expensive,
and require highly skilled personnel and specialised technical equipment.
2 Reviewed in Mabey D et al. (2004). Diagnostics for the developing world. Nature Reviews Microbiology 2, 231-240.

?

The design and development of diagnostic tests
completed can the test reach the market. In
suitable for use in LMIC has to take account of
some cases, private companies can wait up to
a number of factors. At present the majority
two years before regulatory approval is given
of tests are designed in high-income countries
for sale of a test in LMIC, creating significant
(HIC) and are not suitable to the local context
delays in availability.
of many LMIC. For instance, there may be no

distilled water, a lack of refrigerators or freezers
Commercial companies have a relatively poor
to store reagents and/or tests, and conditions
track record of developing diagnostics aimed
of high humidity and temperature, which may
at LMIC, mostly due to the perceived limited
affect the performance of tests designed for
market and lack of profitability. There are also
use in HIC. Many companies do not guarantee
barriers to the development of diagnostics
the results of rapid tests for tropical diseases,
within the public sector, including:
such as malaria, when they are stored at
clinical trials of a diagnostics test.
that these tests are most frequently used in

clinics where the ambient temperature exceeds
Difficulties in obtaining funding for

technology and assay development, and/or
temperatures above 30C, despite the fact

A focus on the number of research papers
this. Where tests are available, there may be
published within academia, which may
difficulties in assuring test quality, sustainable
disadvantage more applied diagnosticsfocused research and development.
adoption, and clinical impact, given the weak

infrastructure in many LMIC health systems.
The high investment costs associated

with research into diagnostics to detect
Further challenges are presented by the lack
infectious agents such as HIV or TB,
of equipment and infrastructure present at
which require specialised laboratory
diagnostic test sites and laboratories. Distilled,
containment facilities.
deionised water and laboratory equipment are
Difficulty for small start-up or spin-out
often required to prepare lyophilised reagents,
companies in obtaining funding for
yet assessments of diagnostic test sites in LMIC
validation and verification of a new test
show that:
following proof-of-concept studies. Delays
25% of sites do not have pipettes
in funding these studies can create a gap in
that measure volumes under 1ml.
the diagnostic development process.
Over 50% of sites have no
A lack of collaboration between academia
biosafety cabinet.
and the diagnostics industry to translate
25% of sites have no distilled
research advances into practical diagnostic
deionised water.
tests that can be manufactured on a large
Over 50% do not have air conditioning
scale at low cost and high quality.
to reduce temperature.3
In addition, failure to store tests at the
Nevertheless, point-of care, rapid diagnostic
appropriate temperature can markedly
tests (RDTs) for a range of infectious diseases,
affect quality.
such as malaria, HIV, syphilis and chlamydia

have been successfully developed (see Box 2),
In practice, the development of diagnostic
and use of RDTs is growing in LMIC.
tests is a multi-step process. Technology

development, assay development, validation,
Key considerations in the design of RDTs
clinical trials and regulatory approval are all
are sensitivity and specificity, which define
required to develop an effective diagnostic test.
clinical effectiveness. Researchers face many
Only once the final regulatory stage has been
challenges in optimising strategies that refine
3 Data presented by Dr Helen Lee at the Academy of Medical Sciences' workshop, Global health diagnostics: research, development and regulation.
these parameters. In recent years, studies
useful in LMIC. Such methods do not require
have aimed to improve the sensitivity of RDTs
sophisticated equipment for thermal cycling,
through the amplification of detection signals.
and involve a simpler detection process that
This has been effective, for example, at
does not require specialised equipment and
improving the sensitivity of tests that detect
laboratory infrastructure. The advent of
the surface antigen of Hepatitis B.
simpler preparation processes would make

point-of-care nucleic acid tests more feasible
RDTs based on amplification of the relevant
in all settings.
nucleic acid are also attractive, since their

high sensitivity and specificity facilitates the
In optimising the sensitivity of diagnostic tests,
detection of the pathogen in non-invasive
it is important to remain aware that greater
specimens such as urine and saliva. At present
sensitivity does not always translate into benefits
however, currently available nucleic acid-
for patients. In some cases, a less sensitive, but
amplification based tests are not feasible
more rapid, test may actually result in treatment
for use in LMIC, since most require multiple
of a greater number of patients. For instance,
sample preparation steps: even the simplest
tests based on nucleic acid amplification
test requires 7 individual steps. Expensive
technology are highly sensitive, but results
reagents, specialised laboratory infrastructure,
cannot be given to the patients at the same visit,
complex equipment and training are also
requiring patients to return to the clinic for the
required. The interpretation of results can
appropriate treatment. Thus:
present challenges, since the nucleic acid of
Assuming that a nucleic acid amplification
pathogens can remain in the body for several
test has a sensitivity of 95%, but that only
weeks following clearance of an infection.
70% of patients return to the clinic due to
Notably, methods that use a single temperature
the delay in obtaining the test result, the
for nucleic acid amplification, such as loop-
appropriate treatment would be prescribed
mediated amplification, may be particularly
for 66.5% of patients.
Box 2 Case Study: development of a rapid diagnostic test for Chlamydia

In LMIC there is a pressing need for RDTs to diagnose STIs. For instance, there are
approximately 90 million new cases of Chlamydia trachomatis infection worldwide each year.
Chlamydia is a major cause of infertility, but the infection is largely asymptomatic so few
infected individuals are treated, despite the availability of cost-effective treatments. A novel
RDT, developed by the Diagnostics Development Unit (DDU) at the University of Cambridge,
requires no instrumentation and uses non-invasive samples, such as first-void urine collection,
using a simple disposable device. Sample extraction takes less than one minute and results are
obtained in 25 minutes via a colour change on a dipstick. An evaluation showed that the test
has a sensitivity of 84% compared to the gold standard DNA amplification test, which surpasses
the performance of currently available Chlamydia RDTs.4
A Chlamydia screening programme carried out in the Philippines using a new RDT identified that
28% of sex workers, and 6% of patients at obstetrics and gynaecology clinics, were infected.
In antenatal clinics in Western Samoa, 29% of patients were found to be positive for Chlamydia.
Despite its clinical effectiveness, widespread use of this test in LMIC is lagging, in part, owing
to cost. Greater adoption of affordable and high-performance RDTs and treatments is crucial to
preventing spread of this STI.
10
4W
isniewski CA et al. (2008). Optimal method of collection of first-void urine for diagnosis of Chlamydia trachomatis infection in men. Journal of
Clinical Microiology 46(4), 1466-9, Mahilum-Tapay L et al. (2007). New point of care Chlamydia rapid test - bridging the gap between diagnosis
and treatment: performance evaluation study. British Medical Journal 335 (7631), 1190-4.

?
However, an RDT with a sensitivity of 80%
In the future, tests that combine the detection
that gives a rapid result whilst patients
of multiple analytes may become increasingly
are on site - and thus assures that 100%
useful. The multiplex diagnostic system currently
of patients who test positive are treated
available to detect HIV, Hepatitis B virus and
- would result in 80% of patients being
Hepatitis C virus is effective, and similar
managed appropriately. In this case,
developments in RDTs that detect more than one
the provision of immediate treatment
pathogen would be particularly useful in LMIC. It
to infected patients would prevent the
should be noted, however, that such an approach
development of complications and interrupt
might offer little incentive to the private sector,
the chain of transmission in a greater
given the greater profit to be gained from
proportion of
patients.5
supplying multiple individual RDTs.
5G
ift TL (1999). The rapid test paradox: when fewer cases detected lead to more cases treated: a decision analysis of tests for Chlamydia
trachomatis. Sexually Transmitted Diseases 26(4), 232-40.
11
12
4. Access to Diagnostics
4. Access to diagnostics
The marked imbalance of resources available
individuals that access treatment, and the
for the purchase and utilisation of diagnostic
proportion of individuals that are treated,
tests between LMIC and HIC has created
are not always equivalent. This disparity is
substantial inequalities in access to diagnostics.
particularly evident for the treatment of STIs
In addition, since the majority of diagnostic
such as congenital syphilis. In 1999, there were
tests are developed in HIC, many tests are
approximately 4 million new cases of syphilis
optimised for pathogen subtypes that are
involving adults in sub-Saharan Africa alone,
common in HIC, rather than those prevalent
and it is estimated that around half a million
in LMIC. For instance, the majority of
babies die of syphilis in this region each year.6
commercially available tests for HIV have been
Yet syphilis and its sequelae can be effectively
optimised for subtype B, the most prevalent
managed, if the appropriate diagnosis is made.
variant in the USA and Europe. The distribution
Estimates around the diagnostic provision for
of different HIV subtypes also varies markedly
the prevention of congenital syphilis in LMIC
around Africa. Thus, to meet the needs of
indicate that:
HIV diagnosis in LMIC, diagnostic tests need
Approximately 75% of infected women
to be optimised for the detection of subtypes
access care at an antenatal clinic but only
prevalent in particular regions.
50% access the clinic early in pregnancy

(it is important that women are screened
Poor access to healthcare and a lack of
and treated before the end of the second
affordable treatments compound the lack of
trimester to avoid adverse outcomes of

pregnancy from syphilis).
tests available to detect strains and species

of pathogens prevalent in LMIC. Individuals
Only a proportion of women - around 25%
who are most at risk are often the least able to
- are tested for syphilis owing to a lack of
afford a diagnosis. It is for this reason that RDTs
availability of the appropriate diagnostics.
are especially effective in LMIC: the use of RDTs
Many women do not return to the clinic,
enables test results to be more closely linked to
resulting in a further reduction in the
on-the-spot treatment, removing the need for
proportion of infected women who are
patients to re-visit health services over weeks
actually treated.7
or months. The widespread use of RDTs could

therefore revolutionise treatment provision and
It is estimated that the provision of affordable
reduce morbidity and mortality in LMIC.
RDTs for syphilis would enable 75% of infected

women to be treated, which would make a
Currently, even in cases where individuals
substantial impact on perinatal mortality due to
access health services, the proportion of
congenital syphilis.
6W
orld Health Organization (2001). Global prevalence and incidence of selected curable sexually transmitted infections: overview and estimates.
WHO. Geneva, World Health Organization (2005). Projections of mortality and burden of disease to 2030. WHO, Geneva.
7 Data presented by Professor Rosanna Peeling at the Academy of Medical Sciences' workshop, Global health diagnostics: research, development
and regulation.
13
14
5. USE OF DIAGNOSTIC TESTS IN PRACTICE

?
5. Use of diagnostic tests in practice

In practice, the accuracy of RDTs is dependent
suggesting that, in many cases, presumptive
on many variables. In the case of RDTs
diagnosis could prevent treatment for the true
for malaria, performance depends on the
cause of illness.
Plasmodium species that is present, the level of

parasitaemia, and the sensitivity and specificity
The lack of credible data in product inserts,
of the test.8 A recent study reported that the
and the lack of validation data available
sensitivity and specificity of malaria RDTs varied
from field trials, present challenges to policy
considerably, both between high- and low-
makers. It may not be clear which test is the
transmission areas, and according to the month
most sensitive, specific and cost-effective,
of test, age of patient and presence/absence of
and decisions may therefore be guided by
fever during
consultation.9
cost alone. This mistrust and lack of data

underscores the need to improve quality
Importantly, false negative and false positive
assurance and regulatory processes to increase
results can be obtained using poor quality
confidence in diagnostic tests and to ensure
RDTs. In addition, in high-transmission areas,
that procurement and clinical decisions are
the Plasmodium falciparum-specific protein
evidence-based (see section 6). Education,
histidine rich protein 2 (HRP2) from previous
supervision and training of clinicians and health
infections can persist in the bloodstream for
workers are important components of any RDT
several weeks, leading to a false positive result.
introduction programme, in addition to effective
Furthermore, RDTs for malaria that test for
communication of data to decision makers.
HRP2 do not detect malaria caused by other

species. Thus appropriate use and interpretation
An additional consideration is the need to take
of the results of diagnostic tests is critical.
account of language variations between LMIC in

leaflets and RDT packages. Health professionals
False positive or negative results can greatly
and/or individual users rely primarily on
compromise the confidence of clinicians
product inserts for guidance, and it is the role
in using diagnostic test results to guide
of manufacturers and distributors to ensure
treatment. Manufacturers are often not
that instructions for storage, preparation and
required to supply validated specificity and
interpretation are clear, and suitable for the
sensitivity data in product inserts, which
local and national context.
further exacerbates this mistrust, since claims

of performance may be highly inflated (see
Distribution of tests within LMIC can present
section 6). Thus, even if a negative result is
further challenges. The extent to which RDTs
obtained, health workers may treat patients
are distributed depends largely on the regional
for the suspected disease to avoid a potential
incidence of disease, which can vary markedly
fatality, and possibly waste costly medicines.
between countries. In central and eastern
One study performed in Tanzania using an
Africa, HIV subtype A is the most prevalent,
HRP2-specific RDT demonstrated that 54% of
whereas in southern Africa, subtype C is the
individuals testing negative for malaria were
most prevalent, with CRF-02-AG the most
treated for malaria, despite the high sensitivity
prevalent in western Africa. Differences in the
(94%) and specificity (89%) of the chosen
length of the diagnostic supply chain between
RDT.10 In addition, the study showed that over
LMIC will affect the storage facilities and health
90% of prescriptions for antimalarial drugs
system infrastructure required, and existing
in low or moderate transmission areas were
capacity may be variable between and within
given to patients with a negative test result,
different LMIC.
8O
chola LB et al. (2006). The reliability of diagnostic techniques in the diagnosis and management of malaria in the absence of a gold standard.
Lancet Infectious Diseases 6, 582.
9 Abeku et al. (2008). Determinants of the accuracy of rapid diagnostic tests in malaria case management: evidence from low and moderate
transmission settings in the East Africa highlands. Malaria Journal 7, 202-212.
10 Reyburn H et al. (2007). Rapid diagnostic tests compared with malaria microscopy for guiding outpatient treatment of febrile illness in Tanzania:
randomised trial. BMJ 334(7590), 403.
15
16

The tightening of government regulatory
highlighting variations in performance between
requirements for drugs utilised in LMIC has done
geographic regions, seasons and patients, in
much to improve the quality and consistency
addition to identifying practical issues such
of drug trial methodology, and assessments of
as the storage conditions required, shelf life
efficacy and safety. However, at present, few
and user applicability. To date, a number of
national and international regulations exist for
field studies have been carried out for RDTs,
the evaluation of diagnostic tests important to
particularly for malaria, but methodologies,
LMIC and no single body has responsibility for
reference standards and study populations vary
assuring quality standards. Variations in quality
substantially. A range of factors affects the
standards are evident between RDTs that detect
quality of trials, such as:
infectious diseases in LMIC, and manufacturers
are able to make inflated claims of clinical
appropriate setting, with the target
effectiveness (see Box 3).
population for which the test is intended.

An independent evaluation of 8 of the 20

commercially available RDTs for dengue
Conduct of the test evaluation in the
Design of the evaluation according to the

purpose of test use.
Sample size.
virus demonstrated that: only two tests
Blinding.
had sensitivities over 50%; none accurately
The gold standard reference utilised
distinguished between primary and secondary
in trials.
dengue infections; and test performance

deteriorated following storage for 3 months
Large-scale trials and quality assurance
at high ambient temperatures.11 Similar
studies of diagnostic tests need to be
disparities between claims and actual
performed according to agreed guidelines in
sensitivities have been found for TB serology
the appropriate context, to obtain reliable,
and Gonorrhoea diagnostic tests.
high quality data. Consistent, effective

methodologies combining tests in the
Inaccuracies can be improved through field
laboratory and in clinical practice are required,
trials and evaluations; these are crucial to
alongside comparative analyses between
Box 3 Variations in global diagnostic regulatory standards

Of 85 countries that responded to a World Health Organization (WHO) questionnaire, just 48%
regulate diagnostic tests for infectious diseases outside of tests used for blood screening. The
data obtained highlight substantial variation in the regulation of RDTs around the world:

The European and American regions showed the highest level of regulation, although
clinical evaluations were not always included and marked variations were evident in the
robustness of evaluations.
Further details provided by individual countries indicated that:

83% and 92% of respondent countries regulate HIV and Hepatitis diagnostics respectively,
yet just 42% regulate diagnostics for STIs and only 13% of countries regulate diagnostics
for TB and malaria.
The costs associated with evaluations of diagnostic tests were markedly variable, ranging
between USD2,000 to USD2,000,000.
One particular evaluation assessed performance of the diagnostic test in just 15 patients.12
11 B
lacksell et al. (2006). The comparative accuracy of 8 commercial rapid immunochromatographic assays for the diagnosis of acute dengue virus
infection. Clinical Infectious Diseases 42(8), 1127.
12 World Health Organization (2006). Diagnostics for tuberculosis: global demand and market potential. Annex: Regulation of in vitro diagnostics: a
global perspective. Geneva: WHO, reviewed in Peeling RW et al. (2006). Rapid tests for sexually transmitted infections (STIs): the way forward.
Sexually Transmitted Infections 82(Suppl V), 1-6.
17
diagnostic tests. The use of standardised
enable information to be shared effectively,
specimens or reagents, against which test
and greater research capacity would facilitate
quality can be compared, would enable quality
studies into the cost-effectiveness of different
testing of RDT batches, to account for any
tests, and communication of outcomes to
deterioration during transit.
decision-makers.
To this end, WHO has partnered with FIND
WHO/TDR is playing a crucial ongoing role
and other agencies to develop a three-tiered
in evaluating the performance of a range of
approach to test the accuracy and stability of
available diagnostic tests including RDTs. WHO
RDTs for malaria, which includes:
also launched a pre-qualification programme
Product testing to demonstrate
for diagnostics in 2008, which has three
performance characteristics.
components for manufacturers: submission
Post-purchase batch testing.
of a dossier of their product for review by an
The use of positive controls at remote test
expert group; inspection of the manufacturing
sites to ensure that the delivered and
site for good manufacturing practice; and a
stored product has retained the necessary
laboratory evaluation of the performance and
qualities.13
operational characteristics of the diagnostic

test. The building of regulatory capacity and
Recent publications detailing guidelines for the
post-market surveillance are also subsequently
design, conduct and reporting of diagnostic
required.15 Current priorities for the pre-
evaluation studies are a welcome advance.14
qualification programme are tests for malaria

and HIV.
In part, the lack of quality assurance of
18
diagnostic tests is due to the sheer number of
Such strategies are important, since the
RDTs available and the lack of human resource
continued use of inaccurate tests poses a
capacity, infrastructure and financial investment
threat to patient safety, and variation in test
available for evaluation. For malaria alone,
quality erodes confidence in test results and
there are over 60 companies manufacturing
thus inhibits evidence-based treatment.
more than 120 different RDTs. Greater
Furthermore, the inclusion of unreliable tests on
capacity in human resources, equipment, raw
the market discourages reputable commercial
materials and knowledge is urgently required
companies from investing in the development
at diagnostic reference laboratories, to enable
of novel diagnostic tests. Given the enormous
test performance studies to be carried out
number of diagnostic tests available, WHO
in the country in which the diagnostic test
cannot perform all of the required evaluations
will be used. The development of regional
alone and greater capacity for regulation and
and international laboratory networks would
quality assurance will be required.
13 W
HO, WHO/TDR and FIND (2008). Initiative for quality assurance of malaria rapid diagnostic tests. Outline of product testing and associated
protocols. http://www.wpro.who.int/NR/rdonlyres/586DC848-8078-4DDD-85FD-9181E352BF14/0/ProductTestingOverview_final_280208.pdf
14 TDR Diagnostics Evaluation Expert Panel (2007). Evaluation of diagnostic tests for infectious diseases: general principles. Nature Reviews
Microbiology Suppl S17-29. Peeling RW et al. (2007). A guide to diagnostic evaluations. Nature Reviews Microbiology Suppl S2-6.
15 http://www.who.int/diagnostics_laboratory/evaluations/en/

Challenges to the diagnostics industry in the
to treat malaria underscores the importance
development of novel diagnostics important to
of making sure that scarce resources are spent
LMIC include:
only on necessary treatments. At present,
The limited share of the global diagnostics
the global coverage of diagnostic tests is
market generated in LMIC, particularly
approximately 10% - just 2% in sub-Saharan
sub-Saharan Africa, which accounts
Africa. Thus, there are significant opportunities
for approximately 0.35% of the global
for growth in the markets of RDTs.
diagnostics market.

Low profit margins owing to pressure to
As has been the case in the development of
provide diagnostic products to LMIC at
therapeutic drugs to treat infectious diseases
low cost.
such as HIV, TB and malaria, there are
Difficulties in sustaining collaborations and
opportunities for the diagnostics industry to
partnerships between academia, industry
collaborate with others to overcome obstacles
and multilateral health initiatives.
to diagnostics research and development.
The plethora of counterfeit and ineffective
For instance:
diagnostic tests available on the market
Greater global co-ordination between
in LMIC, which discourages reputable
academia, funding bodies, the diagnostics
companies from investing in the
industry, pharmaceutical industry and
development of novel diagnostics.
other stakeholders, together with FIND,
A lack of global pressure and advocacy
would ensure that the development
to develop and regulate diagnostic tests
of RDTs follows a systematic and
relevant to LMIC.
co-ordinated process.

The development of global product
Despite these barriers, there is substantial
development partnerships would accelerate
scope for greater development and use of
the development of clinically effective
diagnostics, especially RDTs in LMIC, given the
diagnostics suitable for use in LMIC, similar

to drug and vaccine development.
appropriate financial support. For instance,

estimates based on the WHO World Malaria
Greater collaboration between academia
Report 2008 highlight that approximately
and the diagnostics industry in HIC and
152 million cases of malaria were clinically
LMIC would facilitate the development
confirmed using RDTs or microscopy in 2006,
of diagnostics of benefit to both HIC
compared to 82 million treatment courses
and LMIC, for instance TB, STIs such as
prescribed.16
Additionally, whilst the majority
of diagnoses were made using microscopy in
chlamydia, and NCD such as diabetes.

The development of diagnostics and
2006, RDT use has been steadily rising since
therapeutic drugs linked to the same
2000. The use of RDTs for malaria alone is
disease would benefit both the company
estimated to have increased from 2.9 million
and patients in the relevant countries.
RDTs in 2000 to 28.3 million in 2005.17
Co-ordinated delivery of the diagnostic and

treatment as a combined package might
The significant rise in the use of more costly
also facilitate more effective dissemination
artemisinin-based combination therapy (ACT)
into the health system.
16 Data gathered from World Malaria Report 2008. Geneva, WHO, 2008; Roll Back Malaria (RBM) Commodity database.
http://www.rollbackmalaria.org/gmap/1-3.html,
17 http://www.wpro.who.int/NR/rdonlyres/A15EBA35-91E1-4D8F-9798-5352CEBC7395/0/20_May_2007_RDT_Forecast_report.pdf
19
?
20

CONCLUSIONS
?
Conclusions
To date, efforts to address the burden of
by stimulating innovative developments in RDTs
infectious diseases in LMIC have largely
of importance to LMIC, particularly:
focused on new therapeutic interventions,
been comparatively neglected. As a result,
specialised laboratory equipment.
obtain a result, which can reduce the number

spread of disease.
The ability to conduct the test without

the need for local reagents/water and/or
expensive reagents, and take days or weeks to

of patients who are treated, and exacerbate the
A reduction in requirement for multiple

preparation steps.
of LMIC. Many diagnostic tests require

skilled personnel, specialised equipment and
The ability to be stored for long periods

without refrigeration.
current diagnostic methodologies are often

inappropriate to local needs and contexts
The ability to function above 30C and at

high humidity.
whilst the importance of diagnostics has
The ability to detect multiple pathogens, or

to distinguish between different pathogens
and/or strains and subtypes.
Yet, results from diagnostic tests guide the

majority of healthcare decisions and are
Importantly, there has been a focus on
therefore critical to addressing the health
developing RDTs for infectious diseases at
burden in LMIC. In particular, the advent of fast,
the expense of tests for non-communicable
accurate, point-of-care diagnostic tests holds
diseases and this imbalance will need to be
significant promise to enable evidence-based
addressed in the coming years.
diagnosis and treatment in primary healthcare

settings. Appropriate diagnostic tests also
Access to diagnostics
facilitate: disease surveillance and screening;
A substantial proportion of patients in LMIC
evaluation of the effectiveness of interventions;
lack access to appropriate diagnostics, owing
certification of disease elimination; detection of
to the high purchase cost of many diagnostic
markers of drug resistance; and the facilitation
tests, poor access to healthcare and a lack of
of clinical trials and epidemiological studies - all
diagnostic tests optimised for pathogen subtypes
of which are crucial to addressing the health
common in LMIC. Effective advocacy could play
burden in LMIC. Yet, despite the promise of
an important role in stimulating investment in
rapid diagnostic tests (RDTs), and evidence
research, development and delivery of affordable
of rising demand, there remain a number
diagnostic tests appropriate to LMIC contexts.
of barriers to the implementation of new

diagnostics within LMIC health systems.
In particular, enhanced access to RDTs

resonates with recent calls for a revival
Investment and innovation
of primary health care and the Alma Ata
The limited share of the diagnostics market
Declaration (1978),18 since RDTs facilitate
generated in LMIC and the large number of
diagnosis and treatment at the community
ineffective tests available can discourage
level, without a need for extensive training
reputable companies from investing in the
and specialist equipment. Linking diagnosis to
development of novel diagnostic tests. Many
on-the-spot treatment removes the need for
diagnostics are designed in high-income
many patients to travel long distances to re-visit
countries and therefore fail to take account
healthcare services over weeks or months.
of the needs and priorities of LMIC, or the

variations in prevalence of different pathogen
Regulation and evaluation
strains or subtypes between countries. Greater
Many RDTs are on the market despite a lack of
investment would significantly benefit patients
specificity and/or sensitivity; their performance
18 http://www.who.int/hpr/NPH/docs/declaration_almaata.pdf
21
?
Global
health diagnostics
can vary widely between regions, seasons or
transmission of infectious agents and reduce
patients. Insufficient evidence of accuracy,
the burden of disease.
and inflated claims of test performance by

manufacturers, can lead to misdiagnosis and
The development of a single body that
adverse consequences, waste of precious
represents researchers, clinicians, industry,
resources, and mistrust of test results, which
funders, charities and stakeholders, and which
can all compromise patient safety and affect
holds responsibility for leading advocacy and/or
RDT cost-effectiveness. Decision-makers may
the implementation of regulatory policy would
base purchase decisions on cost alone in the
also be a welcome advance.
absence of robust sensitivity or specificity data.

Infrastructure and capacity
Effective communication between researchers,
Underpinning all of the factors described
clinicians and decision makers in LMIC will be
above is a need to strengthen human resource
needed to overcome these obstacles. Moreover,
capacity to facilitate greater academic
improved regulation and quality assurance
research into the development of diagnostics,
of RDTs would greatly enhance the quality,
to improve evaluations of RDT performance,
accuracy and consistency of diagnostic test
and to carry out cost-effectiveness studies
performance, through a requirement for robust
that are directly relevant to local contexts.
clinical trials and laboratory performance
Investment in specialised equipment and
evaluations. At present the lack of regulation
infrastructure capacity in grassroots services,
enables counterfeit and ineffective tests to
such as diagnostics reference laboratories, are
reach the market - on the ground or via the
additional requirements. The role of community
Internet and there is no requirement for
health workers in delivering diagnoses and
manufacturers to provide data detailing the
treatments should be a key consideration, since
sensitivity and/or specificity of the test. This
the use of RDTs in primary care often does
poses serious threats to public health.
not require specialist knowledge or extensive

training. The introduction of pioneering
There is a pressing need for regulatory policies
approaches that bring together mobile
that are proportionate and appropriate to the
telephone and diagnostic technologies also hold
issues on the ground, and not over-prescriptive.
promise in the future.
Requirements for the future should include:

Evaluations of RDTs in clinical practice using
Advances in research, development and
robust, consistent methodologies.
delivery of diagnostics require a greater focus
Comparative analyses between tests using
on partnerships and collaborations. Innovative
appropriate reference standards.
approaches that bring together academia,
Quality testing of RDT batches following
the diagnostics industry, the pharmaceutical
delivery and storage.
industry and the clinical community possibly in regional consortia - could catalyse
22
A World Health Assembly resolution on the
developments in RDTs. North-South and South-
global regulation of diagnostic tests would
South partnerships could play a crucial role in
provide a crucial policy framework for
facilitating knowledge exchange, education,
improvements in the quality of diagnostic
training and advances in research and
tests sold and used around the world.
development of RDTs. Collaboration between
Advances in the accuracy and clinical
pharmaceutical and diagnostic companies
effectiveness of diagnostic tests would enable
would also link diagnosis and treatment of
a greater proportion of patients to be treated
disease and thus lead to more accurate and
appropriately, which would interrupt the
effective patient care.

CONCLUSIONS
?
Key points

The use of accurate, safe and affordable diagnostic tests has a critical role to play in
addressing the health burden in LMIC. In particular, point-of-care diagnosis using rapid
diagnostic tests that are appropriate to LMIC contexts could revolutionise diagnosis and
treatment in primary healthcare settings. Research and development have a crucial
role to play in the generation of appropriate diagnostics for both infectious and noncommunicable diseases.
Effective advocacy is needed to secure greater investment in: research, development and
delivery of diagnostic tests; infrastructure; equipment; and human resource capacity.
Clearer and more precise data are needed regarding the performance, quality, accuracy and
cost-effectiveness of RDTs in relation to the LMIC contexts in which they are used.
Clear communication of data to decision makers and health professionals is required to

enable evidence-based treatment and policymaking, and to enhance confidence in the use
and application of diagnostic tests.
A tightening of regulatory requirements is needed, to improve the specificity, sensitivity

and safety of diagnostic tests. A World Health Assembly resolution on global regulation of
diagnostic tests would provide a crucial policy framework for such improvements.
A single global body involving academia, clinicians, the diagnostics industry, pharmaceutical
companies, funding bodies and stakeholders, would play an important role by
providing leadership on behalf of the diagnostics community, and by contributing to the
implementation of regulatory policy.
23
?
Global
health diagnostics
24
ANNEX 1: Meeting programme

?
Annex 1: meeting programme

Global health diagnostics: research, development and regulation
Wednesday 3 December 2008
16.30
Registration
16:45
Opening remarks
Sir Andy Haines FMedSci

16:50
Regulation and evaluation of novel diagnostic tests
Professor Rosanna Peeling, Professor of Diagnostics, London School of Hygiene and

Tropical Medicine and Research Co-Ordinator and Director, Diagnostics R&D, UNICEFUNDP-World Bank-WHO Special Programme for Research and Training in Tropical
Diseases (WHO/TDR)
17:20
Development and application of rapid tests for resource-limited settings

Dr Helen Lee, Principal Investigator and Head of Diagnostic Development Unit,
University of Cambridge
17:50
A private sector perspective on R&D for global health diagnostics
Mr Ian Boulton, Managing Director, TropMed Pharma Consulting Ltd

18:20
Panel discussion
Professor David Mabey FMedSci, Professor of Communicable Diseases, London

School of Hygiene and Tropical Medicine
Mr Jean-Franois de Lavison, President, European Diagnostics Manufacturers

Association
Dr Mark Perkins, Chief Scientific Officer, Foundation for Innovative New Diagnostics
18:55
Closing remarks
19:00
End
25
annex
?
Global2:
health
delegate
diagnostics
list
Annex 2: delegate list

Dr Daniel Agranoff, Clinical Senior Lecturer
Professor Peter Godfrey-Faussett, Professor of
Imperial College London
International Health
Dr Till Bachmann, Chief Operating Officer

Division of Pathway Medicine, University of Edinburgh
Professor Jangu Banatvala CBE FMedSci, Emeritus
London School of Hygiene and Tropical Medicine

Dr Clare Green
University College London
Professor of Clinical Virology
Dr Philip Green, Executive Assistant to the Director
Guys and St Thomas School of Medicine
Wellcome Trust
Dr Martha Betson, Post-Doctoral Research Assistant
Professor Brian Greenwood CBE FRS FMedSci, Professor
Natural History Museum

Dr Eddie Blair, Managing Director
Integrated Medicines
Dr Laura Boothman, Policy Officer
Dr Meredith Bradbury
Technology Strategy Board
Professor Philip Butcher, Professor of Molecular
of Clinical Tropical Medicine

Ms Pamela Hepple, Laboratory Specialist
Manson Unit, Mdecins sans Frontires UK
Dr Richard Horton FMedSci, Editor
The Lancet
Dr Jim Huggett, Senior Research Fellow
Medical Microbiology
Professor Anne Johnson FMedSci, Professor of Infectious
St Georges University of London
Disease Epidemiology and Head, Division of
Dr Carmen Camino, Public Health Specialist

LATH
Dr Mark Carrington, Research Group Leader
Dr Chris Chamberlain, Biomarker Expert
Roche
Dr Jane Crawley
MRC Clinical Trials Unit
Dr Nicholas Dellaportas, Practice Manager
Cassidy Medical Centre, Hammersmith and Fulham PCT
Dr Helen Donoghue, Senior Lecturer
Mr Quinton Fivelman, Business Development Manager
Population Health
Ms Paula Kanikadan
PhD Student
Dr Mallika Kaviratne, Technical Officer
Malaria Consortium
Dr Zahra Khatami FRCPath, Consultant Biochemist
BHR Hospitals
Professor Sanjeev Krishna FMedSci, Professor of
Molecular Parasitology and Medicine
St Georges University of London
Professor Ajit Lalvani, Wellcome Trust Senior Clinical
Research Fellow
Professor Ronald Laskey FRS FMedSci, Honorary
Dr Robert Frost, Senior Policy Officer (FORUM)
Director, MRC Cancer Cell Unit
University of Cambridge, Vice-President
Professor Diana Gibb, Professor of Paediatric
Infectious Diseases
Dr Werner Leber
MRC Clinical Trials Unit
Academic General Practitioner

26
annex

2: delegate list?
Dr Kathy Liddell, Fellow in Law
Dr Hyaatun Sillem, Manager, International Activities
Royal Academy of Engineering
Dr David Lynn, Head of Strategic Planning and Policy
Professor Peter Smith CBE FMedSci, Professor of Tropical
Wellcome Trust
Epidemiology
Dr Georgie MacArthur, Policy Officer

Dr Ruth McNerney, Senior Lecturer
Mr Peter Medway, Director of Operations
IMC Worldwide
Ms Stefanie Meredith, Formerly Director of Public
Health Partnerships
International Federation of Pharmaceutical
Manufacturers and Associations
Dr Helen Munn, Director, Medical Science Policy
Dr Behzad Nadjm, Clinical Lecturer
Ms Katherine Nightingale, Assistant News Editor
SciDev.Net
Dr Paul Newton, Director
Wellcome Trust Mahosot Hospital Oxford University
Tropical Medicine Research Collaboration
Ms Anne-Laure Page, Epidemiologist
Epicentre, Mdecins sans Frontires
Professor Geoffrey Pasvol, Professor of Infection and
Tropical Medicine
Professor Catherine Peckham, Professor of
Paediatric Epidemiology
Institute of Child Health, University College London
Sir Keith Peters FRS FMedSci, Emeritus Regius Professor
of Physic
GlaxoSmithKline
Ms Anita Ramesh, PhD Student
Dr Steven Reid, Project Manager, CD4 Initiative

Dr Val Snewin, International Activities Manager
Wellcome Trust
Mr Jose de Sousa Figueiredo, Post-Graduate
Research Assistant
Natural History Museum
Dr David Thompson, Clinical Lecturer and Co-Director of
the Oxford Centre for Monitoring and Diagnosis
University of Oxford
Alex Timusiine, MSc Student
Institute of Child Health, University College London
Professor Richard Trembath FMedSci, Professor of
Medical Genetics
Guys Hospital
Professor Elizabeth Trimble CBE, Professor of Clinical
Biochemistry
Queens University Belfast
Professor Jonathan Weber FMedSci, Head, Division
of Medicine
Dr Alison Webster, Director
Infectious Diseases Medicine Development Centre
GlaxoSmithKline
Dr Jimmy Whitworth, Head of International Activities
Wellcome Trust
Professor Roger Williams CBE FMedSci, Director
Dr Penny Wilson, Diagnostic Specialist
Technology Strategy Board
Dr Maria Zambon, Head
Respiratory Virus Unit, Health Protection Agency
Professor Alimuddin Zumla, Director,
Centre for Infectious Diseases and International Health,
27
?

10 Carlton House Terrace
London, SW1Y 5AH
Tel: +44(0)20 7969 5288
Fax: +44(0)20 7969 5298
E-mail: info@acmedsci.ac.uk
Web: www.acmedsci.ac.uk
28

Global Health Diagnostics: Research, Development and Regulation

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Global Health Diagnostics: Research, Development and Regulation

Uploaded by

Copyright:

Available Formats

Global health diagnostics: research, development

The Academy of Medical Sciences

ISBN No: 1-903401-20-8

Global health diagnostics: research, development

3. Design and development of diagnostic tests

5. Use of diagnostic tests in practice

6. Regulation and evaluation of diagnostic tests

7. Challenges and opportunities for the diagnostics industry

Annex 1: meeting programme

Annex 2: delegate list

Global health diagnostics

Panellists included: Professor David Mabey

held by the Academy of Medical Sciences

FMedSci, London School of Hygiene and

on Global health diagnostics: research,

Tropical Medicine; Mr Jean-Franois de

development and regulation on 3 December

Lavison, European Diagnostics Manufacturers

2008 at the Wellcome Collection Conference

Association; and Dr Mark Perkins, Foundation

Centre in London. The workshop aimed to:

for Innovative New Diagnostics (FIND). The

Raise awareness of the importance of

meeting was attended by 60 invited guests

diagnostics for tackling global health issues.

representing academia, industry, medicine,

Highlight the range of barriers to research,

publishing, research funders and other

development and regulation of global

stakeholders. A full programme and delegate

Highlight the latest research and

The Academy of Medical Sciences is extremely

Identify areas where further activity may

grateful to speakers and attendees for their

contributions to this event. This report captures

The meeting was chaired by Sir Andy Haines

from presentations and discussions on the day,

FMedSci, Director of the London School of

Hygiene and Tropical Medicine, and included

presentations and a panel discussion with key

Design and development of diagnostic tests

experts in the field. Presentations were given

by: Professor Rosanna Peeling, London School

Access to diagnostics in LMIC.

of Hygiene and Tropical Medicine and UNICEF/

Use of diagnostic tests in practice.

UNDP/World Bank/WHO Special Programme

Regulation and evaluation of

for Research and Training in Tropical Diseases

Challenges and opportunities for the

Pharma Consulting Ltd. Three key topics

The report is intended for researchers, research

Research into novel diagnostics.

funders, policymakers and other stakeholders.

Challenges to the evaluation and regulation

Perspectives from the private sector.

Global health diagnostics

Many diagnostic tests remain inappropriate

health have largely focused on the development

to the infrastructure and contexts of LMIC.

and delivery of therapeutic interventions,

A lack of access to diagnostic tests

whilst the value of diagnostics has been

3. Design and development of diagnostic tests